Migraines are widespread in the population and can have a significant impact on an individual's health and quality of life. In the U.S. alone, 18% of women and 6% of men report having had at least one migraine episode in the previous year (Silberstein, “Migraine”. Lancet 2004; 363:381-391). Migraines can also have an economic impact due to medical expenses and reduced or lost work productivity. Migraines generally afflict young adults, the main population of the workforce. The unpredictable or periodic nature of migraines can result in temporary lost work productivity or extended work disability, let alone interfere with an individual's normal activities.
A migraine generally results in a specific type of vascular headache characterized by moderate to intense head pain, often described by sufferers as pulsing or throbbing, lasting up to 4-72 hours when untreated. The pain of a migraine is often localized to one side of the head (i.e., unilateral), although the pain may be present on both sides of the head (i.e., bilateral). Migraine headaches are also accompanied by at least one or more symptoms including extreme sensitivity to stimuli (e.g., light and sound), gastrointestinal upset and visual disturbances or aura.
Because the events that contribute to migraine are still not well understood, prevention and trigger avoidance are typically not effective in controlling migraines. More typically migraine sufferers rely on symptomatic control or abortive treatments for relieving individual headaches. Despite continuing advances in migraine treatment, most existing treatments work slowly, have limited efficacy, or have undesirable side effects.
Sumatriptan and other triptan molecules represent the dominant standard of care against migraine attacks. Sumatriptan is a serotonin (5-HT1B/1D) receptor agonist that causes constriction of cranial blood vessels. Sumatriptan is widely prescribed in the United States and around the world as a treatment for acute migraine headaches with or without aura in adults. Sumatriptan succinate is marketed commercially as Imitrex® in tablet, nasal spray and injectable dosage forms. Doenicke et al., Lancet, 1988, Vol. 1, 1309-11; and Feniuk & Humphrey, Drug Development Research, 1992, 26, 235-40. Other marketed triptans that act as 5-HT1B/ID receptor agonists include rizatriptan, eletriptan, zolmitriptan, naratriptan, almotriptan, and frovatriptan.
The triptans are reported to suffer from several disadvantages, including migraine reoccurrence. In particular, it has been observed that the migraine in patients who are treated with sumatriptan often reoccurs within 8 or 24 hours of an initial treatment. To overcome this problem, Plachetka et al., in U.S. Pat. No. 6,060,499, have proposed combining the sumatriptan with a long acting NSAID such as naproxen sodium. According to Plachetka, “the addition of a long-acting NSAID to a 5-HT agonist extends the period of effective anti-migraine action and prevents the relapse headache from occurring (or “rebound migraines”), whatever is its cause.” See also Smith et al., HEADACHE 2005; 45:983-91; and U.S. Pat. No. 6,384,034 to Simitchieva et al. (proposing a combination of sumatriptan or rizatriptan and a selective COX-2 inhibitor such as rofecoxib or celecoxib.))
The triptans can also suffer from a slow pharmacokinetic profile and, consequently, a delayed therapeutic effect. In healthy adults, it requires on average 2.0 hours after administration for the sumatriptan to reach its maximum concentration in the plasma. During a migraine attack, the absorption slows even further, and maximum blood concentrations are not reached until 2.5 hours after administration. See prescribing information for Imitrex® tablets. Investigators have proposed that this increased absorption time is caused by a slowing of the gastrointestinal tract, but therapeutic interventions based on such delayed gastrointestinal motility remain evasive. See De Ponti et al., FUNCT NEUROL. 2000; 15 Suppl 3:43-9.
To overcome this delayed action, Maichle et al. (WO 2007/127207) have proposed combining the triptan with diclofenac, in a specially formulated dosage form that hastens the absorption of diclofenac in the GI tract. The combination is said to provide quick relief through the diclofenac, in as little as 15 minutes, before the triptan can take effect. While the dosage form has some utility, it still fails to solve the problem of triptan absorption, and the delayed therapeutic effect attainable by the triptan.
Accordingly, it is an object of the present invention to improve the absorption rate of triptans and other migraine medications when orally administered. Another object is to improve the absorption rate of triptans and other migraine medications when orally administered during a migraine attack.
Yet another object is to treat the symptoms associated with migraine, using a combined drug regimen, to provide relief greater than that achieved using a triptan or other migraine medication alone.
Thus, another object is the provision of a combined drug regimen that treats one or more symptoms often associated with migraine faster than a triptan or other migraine medication alone, wherein said symptoms are selected from nausea, photophobia, phonophobia, pain, and rebound headache.
In another embodiment the combined drug regimen treats one or more symptoms often associated with migraine better than a triptan or other migraine medication alone, wherein said symptoms are selected from nausea, photophobia, phonophobia, pain, and rebound headache.